A5045655401- Telomeres, Telomerase, and Senescence
- DNA Repair Mechanisms
- Genomics and Chromatin Dynamics
- CRISPR and Genetic Engineering
- Advanced biosensing and bioanalysis techniques
- Genetics and Neurodevelopmental Disorders
- Ubiquitin and proteasome pathways
- 14-3-3 protein interactions
- RNA modifications and cancer
- Epigenetics and DNA Methylation
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Cancer-related gene regulation
- Acute Myeloid Leukemia Research
- Cancer, Hypoxia, and Metabolism
- Nanoplatforms for cancer theranostics
- Muscle Physiology and Disorders
- Plant Molecular Biology Research
- Cardiac Imaging and Diagnostics
- Protein Degradation and Inhibitors
- Hormonal Regulation and Hypertension
- Microbial Natural Products and Biosynthesis
- Mitochondrial Function and Pathology
- Eosinophilic Disorders and Syndromes
- Neuroscience and Neuropharmacology Research
- Cancer Research and Treatments
University of Oxford
2009-2025
MRC Weatherall Institute of Molecular Medicine
2020-2023
John Radcliffe Hospital
2011-2021
Medical Research Council
2011
Syngenta (United Kingdom)
2005
Abstract Fifteen per cent of cancers maintain telomere length independently telomerase by the homologous recombination (HR)-associated alternative lengthening telomeres (ALT) pathway. A unifying feature these tumours are mutations in ATRX. Here we show that expression ectopic ATRX triggers a suppression pathway and shortening. Importantly ATRX-mediated ALT is dependent on histone chaperone DAXX. Re-expression associated with reduction replication fork stalling, known trigger for HR loss MRN...
The chromatin remodeling protein ATRX, which targets tandem repetitive DNA, has been shown to be required for expression of the alpha globin genes, proliferation a variety cellular progenitors, chromosome congression and maintenance telomeres. Mutations in ATRX have recently identified tumours maintain their telomeres by telomerase independent pathway involving homologous recombination thought triggered DNA damage. It is as yet unknown whether there central underlying mechanism associated...
Histone modifications occur in precise patterns and are proposed to signal the recruitment of effector molecules that profoundly impact chromatin structure, gene regulation, cell cycle events.The linked serine 10 phosphorylation lysine 14 acetylation on histone H3 (H3S10phK14ac), conserved from Saccharomyces cerevisiae humans, crucial for transcriptional activation many genes.However, mechanism H3S10phK14ac involvement these processes is unclear.To shed light role this dual modification, we...
The alternative lengthening of telomeres (ALT) pathway is a telomerase-independent mechanism for immortalization in cancer cells and commonly activated low-grade high-grade glioma, as well osteosarcoma. ALT can be under various conditions has often been shown to include mutational loss ATRX. However, this insufficient isolation so other cellular event must also implicated. It that excessive accumulation DNA:RNA hybrid structures (R-loops) and/or formation DNA-protein crosslinks (DPCs)...
Abstract Telomere maintenance is a hallmark of malignant cells and allows cancers to divide indefinitely. In some cancers, this achieved through the alternative lengthening telomeres (ALT) pathway. Whilst loss ATRX near universal feature ALT-cancers, it insufficient in isolation. As such, other cellular events must be necessary - but exact nature secondary has remained elusive. Here, we report that trapping proteins (such as TOP1, TOP2A PARP1) on DNA leads ALT induction lacking ATRX. We...
Cancers result from the accumulation of genetic lesions, but cellular consequences driver mutations remain unclear, especially during earliest stages malignancy. The V617F mutation in JAK2 non-receptor tyrosine kinase (JAK2V617F) is present as an early somatic event most patients with myeloproliferative neoplasms (MPNs), and study these chronic myeloid malignancies provides experimentally tractable approach to understanding tumorigenesis. Introduction exogenous JAK2V617F impairs replication...
Gene transcription responds to stress and metabolic signals optimize growth survival. Histone H3 (H3) lysine 4 trimethylation (K4me3) facilitates state changes, but how levels are coordinated with the environment is unclear. Here, we show that isomerization of at alanine 15-proline 16 (A15-P16) peptide bond influenced by 14 (K14) controls gene-specific K4me3 balancing actions Jhd2, demethylase, Spp1, a subunit Set1 K4 methyltransferase complex. Acetylation K14 favors A15-P16trans...
The SANT domain is a nucleosome recognition module found in transcriptional regulatory proteins, including chromatin-modifying enzymes. It shows high functional degeneracy between species, varying sequence and copy number. Here, we investigate functions vivo associated with two motifs, SLIDE, the Saccharomyces cerevisiae Isw1 chromatin-remodeling ATPase. We show that differences primary structures of SLIDE domains yeast Drosophila melanogaster reflect their different functions. In yeast,...
Hereditary fibrosing poikiloderma (HFP) is a rare human dominant negative disorder caused by mutations in the FAM111B gene that encodes nuclear trypsin-like serine protease. HFP patients present with symptoms including skin abnormalities, tendon contractures, myopathy and lung fibrosis. We characterized cellular roles of using U2OS MCF7 cell lines report here protease interacts components pore complex. Loss expression resulted abnormal shape reduced telomeric DNA content suggesting required...
Approximately 10-15% of human cancers are telomerase-negative and maintain their telomeres through a recombination-based process known as the alternative lengthening (ALT) pathway. Loss alpha-thalassemia/mental retardation, X-linked (ATRX) chromatin remodeller is common event in ALT-positive cancers, but generally insufficient to drive ALT induction isolation. We previously demonstrated that ATRX binds MRN complex, which also be important pathway, molecular basis this interaction remained...
Abstract Hereditary fibrosing poikiloderma (HFP) is a rare human dominant negative disorder caused by mutations in the FAM111B gene that encodes nuclear trypsin-like serine protease. HFP patients present with symptoms including skin abnormalities, tendon contractures, myopathy and lung fibrosis. We characterised cellular roles of using U2OS MCF7 cell lines report here protease interacts components pore complex. Loss expression resulted abnormal shape reduced telomeric DNA content suggesting...
Abstract A key requisite for indefinite growth of cancer cells is the ability to continuously elongate telomeres circumvent onset senescence or apoptosis. In approximately 10 – 15% cancers this achieved through Alternative Lengthening Telomeres (ALT) pathway, a Break Induced Replication (BIR) mediated mechanism telomere copying. ATRX has emerged as tumour suppressor in ALT but its loss insufficient drive induction pathway. Here, we report that depletion and/or DAXX presence various genotoxic...